Currently available treatments for depression mostly act on increasing the synaptic serotonin levels but do not work universally. Neurogenesis (birth of new neurons) in the adult brain occurs naturally, routinely, and may be functionally important. Inhibition of neurogenesis is thought to be linked to depression and may be the explanation for reduced hippocampal volume seen in patients with major depression. Drugs designed to relieve such inhibition of neurogenesis and to enhance the level of neurogenesis in patients with depression may provide treatment at a structural level and become long-acting, next-generation therapeutics. The objective of this proposal is to determine whether neurogenic activity is critical and sufficient for behavioral efficacy in rodent depression models. By screening small molecule libraries with in vitro and in vivo models of hippocampal neurogenesis, several compounds with in vivo neurogenic activity in mice have been discovered by Neuralstem Inc. Proposed here is a research plan to test these novel neurogenic compounds for efficacy as antidepressants, using in vitro and in vivo models of depression. 3 of the compounds with distinct chemical structures will be tested after chronic oral administration of 4 weeks in 3 mouse models of depression: novelty suppressed feeding, forced swim, and tail suspension tests. In vitro studies will be performed to explore potential mechanism-of-action. Ultimately, a neurogenic compound that is safe, orally available, and working through a novel mechanism for the next generation anti-depressant may result from this study.